The current markers used to predict the prognosis or overall survival of cancer patients usually did not have high predictive value or were considered controversial due to conflicting reports (Clin. Cancer Res. 12, 507-515, 2006). That is to say, there are still no reliable markers or a set of diagnostic markers to significantly predict the prognosis or overall survival of cancer patients (J. Exp. Pathol. 86, 347-363, 2005; Oral. Surg. Oral. Med. Oral. Pathol. Oral. Radio. Endod. 102, 67-76, 2006).
Expression of hypoxic markers (HIF-1α, HIF-2α and CA IX) has been repeatedly reported to correlate with the development of therapeutic resistance and worse prognosis in different types of human cancers, including breast cancer, lung cancer, liver cancer, stomach cancer, kidney cancer, prostate cancer and so on (Clin. Cancer Res. 10, 8554-60, 2004; J. Clin. Oncol. 24, 727-35, 2006; Inr. J. Cancer 120, 1451-1458, 2007; Morphol. 14, 78-82, 2006; Lung Cancer 49, 325-335, 2005; World J. Gastroenrerol II, 1705-1708, 2005; J. Heparol 35, 643-649, 2005; Clin. Cancer Res. 12, 5112-5117, 2006; Ann. Surg. 243, 334-340, 2006; Clin. Cancer Res. 13, 7388-7393, 2007; Clin. Cancer Res. 11, 7658-7663, 2005; Melanoma Res. 13, 493-501, 2003). Specifically, tumors with abundant HIF-1 stabilization through intratumoral hypoxia are more likely to develop metastasis and correlate with poor survival (J. Cell 127, 679-695, 2006; Cancer 2, 38-47, 2002; Trends Mol. Med. 8 (4 Suppl), S62-67, 2002), especially in HNSCC (Neck 27, 622-638, 2005) and breast cancer (Cancer Res. 3, 313-317, 2001).
Increased expression levels of EMT regulators (TWIST, Snail, Slug, SIP1, E47, Zeb1) have also been reported to be associated with an aggressive phenotype and worse prognosis in different cancers, including breast cancer, liver cancer, stomach cancer and prostate cancer (Cell 117, 927-939, 2004; Inr. J. Oncol. 27, 1535-1541, 2005; Anticancer Res. 24, 3851-3856, 2004; Oncogene 21, 3241-3246, 2002; Cancer 103, 1631˜1643, 2005; Clin. Cancer Res. 11, 8070-8078, 2005; Clin. Cancer Res. 12, 5369˜5376, 2006; Clin. Cancer Res. 9, 2657-2664, 2003; Pathology 39, 470-475, 2007; Am. J. Pathol. 161, 1881-1891, 2002; J. Pathol. 211, 507-515, 2007; Dig. Dis. Sci. 50, 42-46, 2005; Int. J. Cancer 119, 2098-2104, 2006; Histopathology 50, 648-658, 2007; Cancer Res. 64, 5270-5282, 2004). Specifically, TWIST or Snail overexpression also correlates with a worse prognosis of cancer patients (Cancer Cell 8, 197-209, 2005; Cell 117, 927-939, 2004; Clin. Cancer Res. 12, 5369-5376, 2006; Oncogene 26, 1459-1467, 2007).
Despite the mentioned markers were shown as possible indicators for metastatic potential or worse prognosis of certain cancers, there are still no reports using a combination of markers such as hypoxic and EMT markers to analyze clinical samples and have a high probability of predicting prognosis and overall survival in cancer patients.